The growing population burden of obesity in the U.S. and around the world has been accompanied by a major international epidemic of type 2 diabetes. Research is urgently needed to better understand the links between obesity and the two major mechanisms in the development of type 2 diabetes, i.e., insulin resistance and impaired insulin secretion. Recent preliminary studies have found some strong associations between systemic markers of inflammation and type 2 diabetes, suggesting that inflammatory mediators are involved in the pathogenesis of this disease and may partially account for the metabolic consequences ascribed to obesity. The cytokines tumor necrosis factor-alpha (TNF-alpha) and leptin may play critical roles in these processes. The overall objective of the study is to identify the contribution of TNF-alpha, leptin, and other selected elements of the inflammatory process to the development of type 2 diabetes. To further elucidate pathways that may link pro-inflammatory cytokines with obesity and diabetes, the study will evaluate the role of extrinsic and intrinsic factors hypothesized to modify or contribute to the inflammatory state (atherosclerosis, chronic infections with C. pneumoniae and cytomegalovirus, and sociodemographic influences) as well as factors hypothesized to mediate these associations (free fatty acids, cortisol, acute phase reactants, and endothelial dysfunction). The study will be conducted using existing examination data and stored biologic specimens from a well-characterized, population-based cohort of 15,792 middle-aged African-American and white adults from four U.S. communities (the Atherosclerosis Risk in Communities Study, or ARIC), in which over 1100 new cases of diabetes have been detected over three to nine years of follow-up. More specifically, a nested case-cohort design will be used to select a simple random sample of 600 incident diabetes cases and a cohort stratified random sample of 700 individuals from the study base that gave rise to the cases. New cases of diabetes who present with anti-GAD65 antibodies will be excluded from this sample and later examined separately to characterize risk factors for the development of so-called latent autoimmune diabetes in adults (LADA). In all studies, circulating levels of inflammatory precursors and other analytes will be measured using frozen plasma or serum specimens collected from these participants at the baseline ARIC examination and subsequent follow-up examinations. The ability of these inflammatory elements to predict incident diabetes will be evaluated in time-to-event analyses utilizing proportional hazards models adapted to the case-cohort approach. The investigators state that the study will contribute to an emerging new focus of research in the pathogenesis of type 2 diabetes: the role of chronic inflammation and the innate immune system. They further state that its prospective, population-based nature will support the generalizability of the findings and their application to public health, and that the large sample of African-Americans will provide important new information for this understudied minority population.